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Salsalate improves glycaemia in overweight persons with diabetes risk factors of stable statin-treated cardiovascular disease: A 30-month randomized placebo-controlled trial.

ABSTRACT: OBJECTIVE:To assess long-term efficacy and safety of salsalate to improve glycemia in persons with diabetes risk, who are overweight with statin-treated, stable coronary heart disease. METHODS:Glycemic status was assessed in 192 persons without diabetes at baseline in a pre-specified secondary analysis from Targeting INflammation Using SALsalate in CardioVascular Disease (TINSAL-CVD), a multi-center, double-masked, randomized (1:1), placebo-controlled, parallel clinical trial. RESULTS:Participants were mostly Caucasian males, age 60±7 years, BMI 31.4±3.0 kg/m2 , fasting glucose 92.8±11.0 mg/dL, and HbA1c 5.8±0.3%. Reductions in mean fasting glucose -5.70 mg/dL (95%CI: -7.44 to -3.97 mg/dL, P<0.001), HbA1c -0.11% (95%CI: -0.210 to -0.002%, P=0.046) and glycated serum protein -81.8 ?g/mL (95%CI: -93.7 to -69.9 ?g/mL, P<0.001) were demonstrated in salsalate compared to placebo-assigned groups over 30 months. Reductions in fasting glucose and glycated serum protein were greater with salsalate compared to placebo in participants with prediabetes compared to a normoglycemic sub-group (Pinteraction =0.018). Salsalate lowered total white blood cell counts (mean difference -0.7x103 /?L, 95%CI: -1.0 to -0.4 x103 /?L, P<0.001) and increased adiponectin (mean difference 1.8 ?g/mL, 95%CI: 0.9 to 2.6 ?g/mL, P<0.001) and albuminurea (16.7 ?g/mg, 95%CI: 6.4 to 27.1 ?g/mg, P<0.001) compared to placebo, consistent with previous results for patients with type 2 diabetes taking salsalate for shorter times. CONCLUSIONS:Salsalate improves glycemia in obese persons at increased risk for diabetes, and hence may decrease risk of incident type 2 diabetes. Salsalate may inform new therapeutic approaches for diabetes prevention, but renal safety may limit clinical utility.

SUBMITTER: Salastekar N

PROVIDER: S-EPMC5599319 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Salsalate improves glycaemia in overweight persons with diabetes risk factors of stable statin-treated cardiovascular disease: A 30-month randomized placebo-controlled trial.

Salastekar Ninad N Desai Tanvi T Hauser Thomas T Schaefer Ernst J EJ Fowler Kristen K Joseph Stacey S Shoelson Steven E SE Goldfine Allison B AB

Diabetes, obesity & metabolism 20170706 10

<h4>Objective</h4>To assess long-term efficacy and safety of salsalate to improve glycemia in persons with diabetes risk, who are overweight with statin-treated, stable coronary heart disease.<h4>Methods</h4>Glycemic status was assessed in 192 persons without diabetes at baseline in a pre-specified secondary analysis from Targeting INflammation Using SALsalate in CardioVascular Disease (TINSAL-CVD), a multi-center, double-masked, randomized (1:1), placebo-controlled, parallel clinical trial.<h4> ...[more]

PMID: 28295931

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Project description:Aims/hypothesisChronic sub-acute inflammation contributes to the pathogenesis of type 2 diabetes mellitus and cardiovascular disease. High doses of salicylate reduce inflammation, glucose and triacylglycerols, and may improve insulin sensitivity, suggesting therapeutic potential in impaired fasting glucose and/or impaired glucose tolerance. This trial aimed to evaluate the effect of salsalate vs placebo on insulin resistance and glycaemia in impaired fasting glucose and/or impaired glucose tolerance.MethodsWe conducted a 12 week, two-centre, randomised, placebo-controlled study to evaluate the effect of salsalate (up to 4 g/day) vs placebo on systemic glucose disposal. Secondary objectives included treatment effects on glycaemia, inflammation and cardiovascular risk factors. Seventy-eight participants with impaired fasting glucose and/or impaired glucose tolerance from two VA healthcare systems were enrolled. Randomisation assignment was provided by the coordinating center directly to site pharmacists, and participants and research staff were blinded to treatment assignment.ResultsSeventy-one individuals were randomised to placebo (n = 36) or salsalate (n = 35). Glucose disposal did not change in either group (salsalate 1% [95% CI -39%, 56%]; placebo 6% [95% CI -20%, 61%], p = 0.3 for placebo vs salsalate). Fasting glucose was reduced by 6% during the study by salsalate (p = 0.006) but did not change with placebo. Declines in glucose were accompanied by declines in fasting C-peptide with salsalate. Insulin clearance was reduced with salsalate. In the salsalate group, triacylglycerol levels were lower by 25% (p = 0.01) and adiponectin increased by 53% (p = 0.02) at the end of the study. Blood pressure, endothelial function and other inflammation markers did not differ between groups. Adipose tissue nuclear factor κB (NF-κB) activity declined in the salsalate group compared with placebo (-16% vs 42%, p = 0.005), but was not correlated with metabolic improvements. The frequency of tinnitus was low but tended to be higher with salsalate therapy (n = 4 vs n = 2).Conclusions/interpretationIn summary, salsalate therapy was well tolerated, lowered fasting glucose, increased adiponectin and reduced adipose tissue NF-κB activity. These changes were not related to changes in peripheral insulin sensitivity, suggesting additional mechanisms for metabolic improvement.Trial registrationClinicalTrials.gov NCT00330733.FundingOffice of Research and Development, Medical Research Service, Department of Veterans Affairs and NIH K24 DK63214.

Project description:Rates of hepatocellular carcinoma (HCC) are increasing rapidly due to the epidemic of metabolic dysfunction-associated steatohepatitis (MASH). In addition to increased incidence, emerging evidence suggests that MASH driven HCC is associated with poor survival outcomes potentially due to the complex liver microenvironment which is characterized by hypoxia, steatosis, and fibrosis. Lenvatinib, is a multi-tyrosine kinase inhibitor, that is a standard of care therapy for unresected HCC, but 5-year survival rates are less than 20%. Therefore, developing treatments that inhibit cancer growth kinetics and target the tumor microenvironment to improve the therapeutic response in MASH-HCC are needed. Salsalate is a rheumatoid arthritis therapy that stimulates the AMP-activated protein kinase (AMPK) increasing fatty acid oxidation while reducing de-novo lipogenesis, fibrosis and cell proliferation pathways. Thus, we hypothesized that Salsalate could improve the therapeutic efficacy of Lenvatinib in MASH-HCC. In the current study, we show that treatment of human HCC cells with clinically relevant concentrations of Lenvatinib and Salsalate synergistically suppress proliferation and clonogenic survival, activate AMPK and inhibit the mTOR-HIF1a and Erk1/2 signaling pathways. In orthotopic xenograft and MASH-HCC mouse models Lenvatinib and Salsalate combination therapy suppressed angiogenesis and steatosis and fibrosis. RNA-sequencing revealed combination therapy enhanced mitochondria fatty acid oxidation and suppressed glycolysis, angiogenesis, fibrosis and cell cycle progression with regulatory network analysis suggesting a potential role for Activating transcription factor 3 (ATF3) and ETS-proto-oncogene-1 (ETS1). These data suggest that Lenvatinib and Salsalate combination therapy may have therapeutic potential for MASH-HCC due to effective metabolic rewiring and growth inhibition, leading to improvements in the liver microenvironment and inhibition of HCC proliferation.

Dataset Information

Salsalate improves glycaemia in overweight persons with diabetes risk factors of stable statin-treated cardiovascular disease: A 30-month randomized placebo-controlled trial.

Publications

Salsalate improves glycaemia in overweight persons with diabetes risk factors of stable statin-treated cardiovascular disease: A 30-month randomized placebo-controlled trial.

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